Biomarkers and methods for assessing myocardial infarction and serious infection risk in rheumatoid arthritis patients

Abstract

Provided herein are methods for assessing risk of infection or cardiovascular disease (CVD) in a subject with an inflammatory disease, e.g., rheumatoid arthritis. The methods include performing immunoassays to generate scores based on quantitative data for expression of biomarkers relating to inflammatory biomarkers with or without additional clinical variables to assess infection and CVD risk. Also provided are uses of inflammatory biomarkers for guiding treatment decisions.

What is claimed is: 
     
         1 . A method for assessing risk of infection or cardiovascular disease (CVD) in a subject with an inflammatory disease, the method comprising:
 performing at least one immunoassay on a first blood sample from the subject to generate a first dataset comprising protein level data for at least two protein markers, wherein the at least two protein markers comprise at least two markers selected from chitinase 3-like 1 (cartilage glycoprotein-39) (CHI3L1); C-reactive protein, pentraxin-related (CRP); epidermal growth factor (beta-urogastrone) (EGF); interleukin 6 (interferon, beta 2) (IL6); leptin (LEP); matrix metallopeptidase 1 (interstitial collagenase) (MMP1); matrix metallopeptidase 3 (stromelysin 1, progelatinase) (MMP3); resistin (RETN); serum amyloid A1 (SAA1); tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A); vascular cell adhesion molecule 1 (VCAM1); and, vascular endothelial growth factor A (VEGFA); and   determining a risk score from the first dataset using an interpretation function, wherein said risk score predicts the risk of infection or CVD in said subject.   
     
     
         2 . The method of  claim 1 , wherein the at least two protein markers comprise CHI3L1; CRP; EGF; IL6; LEP; MMP1; MMP3; RETN; SAA1; TNFRSF1A; VCAM1; and, VEGFA. 
     
     
         3 . The method of  claim 1 , wherein the score is compared to a clinical assessment, wherein the clinical assessment is selected from the group consisting of: a DAS, a DAS28, a DAS28-CRP, a DAS28-ESR, a Sharp score, a tender joint count (TJC), and a swollen joint count (SJC). 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the at least one immunoassay comprises a multiplex assay. 
     
     
         6 . The method of  claim 1 , wherein performance of the at least one immunoassay comprises:
 obtaining the first blood sample, wherein the first blood sample comprises the protein markers;   contacting the first blood sample with a plurality of distinct reagents;   generating a plurality of distinct complexes between the reagents and markers; and   detecting the complexes to generate the data.   
     
     
         7 . The method of  claim 1 , wherein the interpretation function is based on a predictive model. 
     
     
         8 . The method of  claim 1 , wherein the inflammatory disease in rheumatoid arthritis (RA). 
     
     
         9 . The method of  claim 1 , wherein the risk of infection is one or more of pneumonia or sepsis and/or the risk of CVD is defined by a composite coronary heart disease (CHD) outcome. 
     
     
         10 . The method of  claim 9 , wherein the CHD is one or more of myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG). 
     
     
         11 . The method of  claim 1  wherein the risk score is combined with at least one test clinical score representing at least one clinical variable. 
     
     
         12 . The method of  claim 11 , wherein said at least one clinical score incorporates at least one clinical variable chosen from age, gender, sex, smoking status, adiposity, body mass index (BMI), serum leptin, and race/ethnicity. 
     
     
         13 .- 14 . (canceled) 
     
     
         15 . A method for recommending a therapeutic regimen in a subject having an autoimmune disorder, the method comprising:
 a) performing at least one immunoassay on a first blood sample from the first subject to generate a first dataset comprising protein level data for at least two protein markers, wherein the at least two protein markers comprise at least two markers selected from chitinase 3-like 1 (cartilage glycoprotein-39) (CHI3L1); C-reactive protein, pentraxin-related (CRP); epidermal growth factor (beta-urogastrone) (EGF); interleukin 6 (interferon, beta 2) (IL6); leptin (LEP); matrix metallopeptidase 1 (interstitial collagenase) (MMP1); matrix metallopeptidase 3 (stromelysin 1, progelatinase) (MMP3); resistin (RETN); serum amyloid A1 (SAA1); tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A); vascular cell adhesion molecule 1 (VCAM1); and, vascular endothelial growth factor A (VEGFA);   b) determining a risk score from the first dataset using an interpretation function, wherein said risk score predicts the risk of infection or CVD in said first subject; and   c) recommending
 i) no therapy regimen if the score is low: or 
 ii) a therapy regimen if the score is high. 
   
     
     
         16 . The method of  claim 15 , wherein the at least two protein markers comprise CHI3L1; CRP; EGF; IL6; LEP; MMP1; MMP3; RETN; SAA1; TNFRSF1A; VCAM1; and, VEGFA. 
     
     
         17 . The method of  claim 15 , wherein the score is compared to a clinical assessment, wherein the clinical assessment is selected from the group consisting of: a DAS, a DAS28, a DAS28-CRP, a DAS28-ESR, a Sharp score, a tender joint count (TJC), and a swollen joint count (SJC). 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 15 , wherein the at least one immunoassay comprises a multiplex assay. 
     
     
         20 . The method of  claim 15 , wherein performance of the at least one immunoassay comprises:
 obtaining the first blood sample, wherein the first blood sample comprises the protein markers;   contacting the first blood sample with a plurality of distinct reagents;   generating a plurality of distinct complexes between the reagents and markers; and   detecting the complexes to generate the data.   
     
     
         21 . The method of  claim 15 , wherein the interpretation function is based on a predictive model. 
     
     
         22 . The method of  claim 15 , wherein the inflammatory disease in rheumatoid arthritis (RA). 
     
     
         23 . The method of  claim 15 , wherein the risk of infection is one or more of pneumonia or sepsis and/or the risk of CVD is defined by a composite coronary heart disease (CHD) outcome. 
     
     
         24 . The method of  claim 23 , wherein the CHD is one or more of myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG). 
     
     
         25 . The method of  claim 15 , wherein the score is low if on a scale of 1-100, the score is less than or equal to about 30. 
     
     
         26 . The method of  claim 15 , wherein the score is high if on a scale of 1-100, the score is greater than about 30. 
     
     
         27 .- 28 . (canceled) 
     
     
         29 . The method of  claim 15  wherein the risk score is combined with at least one test clinical score representing at least one clinical variable chosen from age, gender, sex, smoking status, adiposity, body mass index (BMI), serum leptin, and race/ethnicity. 
     
     
         30 .- 32 . (canceled)